Remote C-H activation of phenyl-substituted alkenes by BH3·THF: Mechanism and applications

Article abstract of DOI:10.1021/ol016215a

(matrix presented) The hydroboration of tetrasubstituted alkenes and, in particular, bicyclic alkenes with BH₃·THF at 50 °C provides, via a highly stereoselective 1,2-rearrangement and a remote C-H activation, a diol in which the relative stere

Full text of DOI:10.1021/ol016215a

ORGANIC
LETTERS
2001
Vol. 3, No. 15
2395-2398
Remote C−H Activation of
Phenyl-Substituted Alkenes by
BH ‚THF: Mechanism and Applications
3
Jesu´s A. Varela, Diego Pen˜a, Bernd Goldfuss,† Kurt Polborn, and Paul Knochel*
Department Chemie, Ludwig-Maximilians-UniVersita¨t, Butenandtstrasse 5-13 (Haus F),
81377 Mu¨nchen, Germany
paul.knochel@cup.uni-muenchen.de
Received June 1, 2001
ABSTRACT
The hydroboration of tetrasubstituted alkenes and, in particular, bicyclic alkenes with BH ‚THF at 50 °C provides, via a highly stereoselective
3
1,2-rearrangement and a remote C−H activation, a diol in which the relative stereochemistry of three centers has been controlled. A mechanistic
study provides general rules for remote C−H activation and leads to new synthetic applications.
The activation of C-H bonds is an important synthetic target
since it opens new possibilities for functionalizing unacti-
vated C-H bonds. Most of these C-H activations have been
performed using transition metal mediated reactions or
transition metal catalyzed reactions.1 Recently, we have
shown that allylic C-H bonds can be stereoselectively
functionalized using a thermal rearrangement of tertiary
organoboranes.2-4 This reaction has been applied to both
open-chain and cyclic systems, allowing the diastereoselec-
tive preparation of a variety of compounds. Thus, the thermal
rearrangement of a tertiary organoborane of type 1 furnishes,
with high selectivity via a tentative borane-olefin complex
2, the more stable secondary organoborane 3. A highly
preferential migration of the hydrogen atom Ha (over Hb)
has been observed. The migration of Ha leads to the most
stable borane-olefin complex (R and Rs are in cis arrange-
ment; Scheme 1). We have also discovered that a remote
C-H activation can be performed with tetrasubstituted
alkenes bearing bulky substituents, such as 4.4 Its treatment
with borane-THF (50 °C; 12 h) provides cyclic organobo-
rane 5, which after oxidative workup (NaOH, H2O2) provides
the diol 6 in 80% yield (Scheme 1). Herein, we wish to
† Organisch-Chemisches Institut der Universita¨t Heidelberg, Im Neuen-
heimer Feld 270, D-29120 Heidelberg, Germany.
(1) (a) Janowicz, A. H.; Bergman, R. G. J. Am. Chem. Soc. 1982, 104,
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B. Angew. Chem. Int. Ed. Engl. 1993, 32, 733. (d) Murai, S.; Kaikiuchi,
F.; Sekiine, S.; Tanaka, Y.; Kamatani, A.; Sonoda, M.; Chatani, N. Nature
1993, 366, 529. (e) Arndtsen, B. A.; Bergman, R. G. Science 1995, 270,
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(2) Some remote C-H activations of organoboranes have been de-
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682, 21. (b) Ko¨ster, R.; Rotermund, G. Angew. Chem. 1960, 72, 563. (c)
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P. J. Am. Chem. Soc. 1999, 121, 6940.
10.1021/ol016215a CCC: $20.00 © 2001 American Chemical Society
Published on Web 07/06/2001

(cis arrangement of the substituents in 5). We therefore
performed a series of experiments which clearly prove the
proposed pathway A. First, we prepared the isomeric alkene
13 and submitted it to the hydroboration conditions used for
the conversion of 4 to 5 (BH3‚THF (3 equiv), 50 °C, 24 h).
We observed after oxidative workup (H2O2, NaOH) the
alcohol 14 only and none of the diol 6; 14 was isolated in
63% yield showing that the intermediate organoborane 12
is not an intermediate of the C-H activation process (Scheme
2). Furthermore, we interrupted the hydroboration of 4 after
Scheme 1
Scheme 2
describe a mechanistic study of this rearrangement. The
results of this study led us to design other systems of type
7, which lead to products of type 8 via a C-H activation.
Remarkably, the conversion of the alkene 4 to the
boracycle 5 produces an intermediate cyclic organoborane
5 bearing the two bulky substituents (Ph and t-Bu) in a cis
arrangement. It should also be noted that this high diaste-
reoselectivity implies that only one of the two diastereotopic
aromatic rings of 4 undergoes C-H activation. To explain
these results, we have envisioned two reaction pathways, A
and B, leading to the cyclic organoborane 5. In the first
pathway, the initial hydroboration product 9, which is
obtained by the reaction of the tetrasubstituted alkene 4 with
BH3‚THF, can undergo a C-H activation of a phenyl ring.5,6
This would lead to the cyclic five-membered boracycle 10.
This heterocycle then undergoes a 1,2-migration,7,8 leading
via borane-olefin complex 11 to the observed product 5.
Interestingly, the coordination of boron to the olefin in 11
during the migration process implies a cis-relationship
between the t-Bu and Ph substituent. The diastereoselective
C-H activation of the aromatic C-H bond of 9 leading to
10 can be readily explained by steric considerations, with
the bulky tert-butyl and phenyl groups being in a trans
relationship in 10.
1 h of reaction time. The oxidative workup of the reaction
mixture provides two products, the final diol 6 (25% yield)
and also the tertiary diol 15 (32% yield). Diol 15 is clearly
the resulting oxidation product of the cyclic organoborane
10 postulated in pathway A. The relative stereochemistry of
6 and 15 was established by X-ray analysis (see Supporting
Information). These results imply that the C-H activation
reaction is especially efficient if a boracyclopentane is
formed. We therefore prepared the trisubstituted alkene 16
and were pleased to find that the hydroboration of 16 with
BH3‚THF and subsequent heating of 16 in THF at 50 °C for
24 h furnished, after oxidative workup, the diastereomerically
pure diol 17 in 60% yield (Scheme 3). We also prepared the
E- and Z-tolyl substituted olefins E-18 and Z-18 and found,
as expected in the case of E-18, a selective activation of the
tolyl ring (19a:19b ) 4:1), whereas with the Z-isomer
(Z-18) a selective activation of the phenyl ring was observed
(19a:19b ) 1:4). The formation of 20% of the other C-H
product can be explained as the alkenes E-18 and Z-18 slowly
isomerize under the reaction conditions at 50 °C.
An alternative pathway (pathway B) is also possible. In
this case, the 1,2-migration leading to the primary orga-
noborane 12 proceeds first and is followed by a C-H
activation of the aromatic ring, leading to the boracycle 5.
Although the 1,2-migration process of 9 to 12 should readily
occur under the reaction conditions, the observed diastereo-
selectivity of the C-H rearrangement is difficult to explain
(5) For a theoretical study of the direct borane-hydrocarbon dehydro-
genation, see: Goldfuss, B.; Knochel, P.; Bromm, L. O.; Knapp, K. Angew.
Chem., Int. Ed. 2000, 39, 4136.
(6) Ko¨ster, W.; Siebert, W. Methoden der Organischen Chemie (Houben-
Weyl), 4th ed.; Thieme: Stuttgart, 1952, 1982; Vol. 13, Part 3a, pp 1-908.
(7) For mechanistic studies on 1,2-boron migrations, see: (a) Wood, S.
E.; Rickborn, B. J. Org. Chem. 1983, 48, 555. (b) Field, L. D.; Galagher,
S. P. Tetrahedron Lett. 1985, 26, 6125.
(8) (a) Brown, H. C.; Zweifel, G. J. Am. Chem. Soc. 1966, 88, 1433. (b)
Brown, H. C.; Bhatt, M. V. J. Am. Chem. Soc. 1966, 88, 1440.
To elucidate the origins of the diastereoselectivities in the
intramolecular C-H activations of 9, the four possible
transition structures of the dehydrogenation processes (cf.
Scheme 2: conversion of 9 to 10, Scheme 4)5 were optimized
and analyzed by frequency computations using the MNDO
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Org. Lett., Vol. 3, No. 15, 2001

They show that the dehydroboration and the rehydroboration
steps have very similar activation energies (TS-1 and TS-2)
but the six-membered boracycle 5 is 5.0 kcal‚mol-1 more
favorable than the corresponding five-membered boracycle
10.
Scheme 3
Scheme 5
method.9,10 B3LYP/6-31G*11 single-point computations using
the IEF-PCM12 solvation model and THF as solvent were
employed to assess the relative energies of the transition
structures.
Scheme 4
According to our study, the presence at least of one bulky
substituent is required for mild remote C-H activation (steric
compression activates the C-H bond). We therefore turned
our attention to bicyclic systems. Thus, the [2.2.1] bicyclic
alkene 20 reacts with BH3‚THF at 50 °C (36 h) and
From these results, the most favorable transition structure
is 9a-TS, in which the two hydrogens that undergo elimina-
tion and the tert-butyl and the phenyl group are trans. This
transition structure would afford the intermediate boracycle
10, which does indeed lead to the observed product 15.
IEF-PCM (THF) B3LYP/6-31G*//MNDO computations
were also performed on the 1,2-migration step (Scheme 5).
Scheme 6
(9) (a) Dewar, M. J. S.; Thiel, W. J. Am. Chem. Soc. 1997, 99, 4907.
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Org. Lett., Vol. 3, No. 15, 2001
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undergoes a selective boron migration leading, after oxidative
workup, to the primary alcohol 21. Further heating of the
alkene 20 and BH3‚THF at 90 °C for 24 h leads to a C-H
activation of the phenyl ring and gives, after oxidation with
H2O2/NaOH, the diol 22 (Scheme 6).
In conclusion, we have determined the mechanism of the
diastereoselective activation of aryl-substituted alkenes. This
allowed us to find several new systems that undergo this
stereoselective C-H activation. We have shown that this new
reaction sequence allows the diastereoselective synthesis of
up to three contiguous chiral centers. Further extensions and
applications are currently underway in our laboratories.
With this system, the C-H activation is not possible in
the initial hydroboration product (trans arrangement of the
boron and the phenyl ring) and this does not allow the
preferential formation of a five-membered boracycle. Instead
a boron migration occurs before the C-H activation (op-
posite reaction sequence as described in Scheme 2). The
corresponding ethyl-substituted alkene 23 undergoes, as
observed in previous cases,3,4 a faster 1,2-migration and
furnishes only one diastereomeric diol (24) with a relative
control of these adjacent chiral centers. The observed
diastereoselectivity (confirmed by X-ray analysis) is readily
explained by the model depicted in Scheme 1. Thus, only
the diastereotopic hydrogen Hb undergoes the dehydrobora-
tion step leading to the less sterically hindered olefin 25.
Other types of tetrasubstituted alkenes undergo the C-H
activation reaction. Thus, the alkene 26 leads, under typical
reaction conditions (BH3‚THF (3 equiv); 50 °C, 24 h), to
the diol 27 as one diastereoisomer in 57% yield.
Acknowledgment. We thank the DFG (SFB 260, Leib-
niz-Programm). J.A.V. thanks the Alexander-von-Humboldt
Stiftung and the European Community (Marie Curie Fel-
lowship of the program “Improving Human Research
Potential and the Socio-economic Knowledge Base” contract
number HPMFCT-2000-00451) for both fellowships. We
thank Chemetall GmbH (Frankfurt) and Degussa-Hu¨ls AG
(Hanau) for generous gifts of chemicals.
Supporting Information Available: Experimental pro-
cedures and spectroscopic data. This material is available
free of charge via the Internet at http://pubs.acs.org.
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